Thursday, April 3, 2014

Current state of regenerative medicine: moving stem cell research from animals into humans for clinical trials

San Diego Regenerative Medicine Institute and Xcelthera INC announce Dr. Parsons several recent publications for our progresses towards clinical translation of human embryonic stem cell research.

Protocol: Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2014, Feb. 6. Chapter in Human Embryonic Stem Cells: Methods and Protocols, 2nd Edition. Springer’s Protocols. DOI: 10.1007/7651_2014_69. PMID24500898.
Public Preview: Developing novel strategies for well-controlled efficiently directing pluripotent human embryonic stem cells (human ES cells) exclusively and uniformly towards clinically-relevant cell types in a lineage-specific manner is not only crucial for unveiling the molecular and cellular cues that direct human embryogenesis, but also vital to harnessing the power of human ES cell biology for tissue engineering and cell-based therapies. Conventional human ES cell differentiation methods require uncontrollable simultaneous multi-lineage differentiation of pluripotent cells, which yield embryoid bodies (EB) or aggregates consisting of a mixed population of cell types of three embryonic germ layers, among which only a very small fraction of cells display targeted differentiation, impractical for commercial and clinical applications. This Springer’s protocol details the step-by-step procedure of PluriXcel technology for lineage-specific differentiation of pluripotent human ES cells, maintained under defined culture systems, direct from the pluripotent stage using small molecule induction exclusively and uniformly to a neural or cardiac lineage. Lineage-specific differentiation of pluripotent hESCs by small molecule induction enables well-controlled high efficient direct conversion of non-functional pluripotent human ES cells into a large supply of high purity functional human neuronal or cardiomyocyte cell therapy derivatives for commercial and therapeutic uses, marking a turning point in cell-based regenerative medicine from current studies in animals towards human trials or first-in-human studies.

Editorial: The designation of human cardiac stem cell therapy products for human trials.  J. Clin. Trial Cardiol. 2014;1(1):02.
Public Preview: For successful pharmaceutical development of stem cell therapy, the human stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials. Moving stem cell research from current studies in animals into human trials must address such practical issues for commercial and therapeutic uses: 1) such human stem cells and/or their cell therapy derivatives/products must be able to be manufactured in a commercial scale; 2) such human stem cells and their cell therapy derivatives/products must be able to retain their normality or stability for a long term; and 3) such human stem cells and/or their cell therapy derivatives/products must be able to differentiate or generate a sufficient number of the specific cell type or types in need of repair or regeneration. Those practical issues are essential for designating any human stem cells as human stem cell therapy products for investigational new drug (IND)-filing and entry into human trials. Our Xcel prototypes of human stem cell therapy products have been developed specifically to address and overcome those major obstacles or issues in clinical applications of human ES cell therapeutic utility, including the benefits in high efficiency, stability, low tumor risk, high purity, high efficacy in repair, as well as safety and large-scale production of high quality human cell therapy products in cGMP facility for commercial and therapeutic uses over all other existing approaches.

Editorial: The openness of pluripotent epigenome – defining the genomic integrity of stemness for regenerative medicine. Int. J. Cancer Ther. Oncol. 2014;2(1):020114. DOI: 10.14319/ijcto.0201.14.
Public Preview: Human embryonic stem cells (human ES cells), derived from the pluripotent inner cell mass or epiblast of the human blastocyst or human embryos, are pluripotent, holding tremendous potential for restoring human tissue and organ function. However, not all pluripotent cells are stem cells. The scientific definition and proof for human pluripotent stem cells are that they have the intrinsic ability of both unlimited or long-term self-renewal and unrestricted differentiation into all the somatic cell types in the human body. So far, there is no evidence that pluripotent cells derived from other sources harboring adult nuclei by transcription-factor- or small-molecule-based reprogramming or somatic cell nuclear transfer, such as iPS cells or pluripotent cells derived from cloned embryos, can maintain prolonged normal stable growth or self-renewal. The artificially reprogrammed adult cells are characterized by the expression of embryonic markers that are initially identified in embryonic tumor/cancer cells and forming teratomas in vivo, which shows these reprogrammed adult cells might be either pluripotent stem cells or pluripotent cancer cells. In contrast, human ES cells are not only pluripotent, but also incredibly stable and positive, as evident by that only the positive active chromatin remodeling factors, but not the negative repressive chromatin remodeling factors, can be found in the open epigenome of pluripotent human ES cells. The openness of pluripotent epigenome differentiates the active pluripotency of normal human ES cells from the repressive pluripotency of abnormal cells, such as the iPS cells reprogrammed from adult cells, pluripotent cells derived from cloned embryos, and pluripotent embryonic carcinoma cells. In view of the growing interest in the use of human pluripotent stem cells, these major drawbacks have raised serious concerns about the genomic integrity of artificially reprogrammed adult cells and, thus, have diminished the utility of reprogramming somatic cells as viable therapeutic approaches. So far, the pluripotent human ES cells remain as the only genetically-stable human pluripotent stem cell source with full-developmental potential in deriving somatic elements for tissue and function restoration.

Critical Review: Current state of regenerative medicine: moving stem cell research from animals into humans for clinical trials. JSM Regen Med 2014;1(1):1005 & Open Access Stem Cell 2014.

Public Preview: Given the limited capacity of the central nervous system (CNS) and the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal tissue and function for neurological and cardiovascular disorders. Derivation of human embryonic stem cell (human ES cells) from the in vitro fertilization (IVF) leftover embryos has brought a new era of cellular medicine for the damaged CNS and heart. Recent advances and technology breakthroughs in human ES cell research have overcome some major obstacles in moving stem cell research from animals towards humans trials, including resolving minimal essential human requirements for de novo derivation and long-term maintenance of clinically-suitable stable human ES cell lines and direct conversion of such pluripotent human ES cells into a large supply of clinical-grade functional human neuronal or cardiomyocyte cell therapy products. Such breakthrough stem cell technologies have demonstrated the direct pharmacologic utility and capacity of human ES cell therapy derivatives for human CNS and myocardium regeneration and, thus, have presented the human ES cell therapy derivatives as a powerful pharmacologic agent of cellular entity for CNS and heart repair. The availability of human stem/progenitor/precursor cells in high purity and large commercial scales with adequate cellular neurogenic or cardiogenic capacity will greatly facilitate developing safe and effective cell-based regenerative therapies against a wide range of CNS and heart disorders. Transforming non-functional pluripotent human ES cells into fate-restricted functional human cell therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of human ES cell-derived cellular products, marking a turning point in cell-based regenerative medicine from current studies in animals towards human trials. 

Thursday, January 2, 2014

The Politicization of Top Scientific Journals --- Who Should I Trust? What Should I Believe?

It has become more and more often we are searching in vain through news channels or sources to try to find out which news agency is telling the truth, only to remember that the news has been brought by some big corporation, no longer owned by the independent spirit of Journalism. It is saying what their financial or political interests tell them to say, not necessarily the truth the public want to know. It has become more and more often we are hearing prestigious university professors, who we suppose to trust, talk like a politician, saying things that they have absolutely no scientific evidence or proof, saying things that the scientific data point otherwise, saying things that distort the scientific process but benefit themselves, saying things that they are not supposed to say as a scientist or physician. It is often the same group of prestigious professors who control those top scientific journals, such as Nature, Science, Cell, that the scientific community trusts most. It is often the same group of prestigious professors, often also editors of those top scientific journals or their close associates/friends, who get published in those top scientific journals with little or no peer-review. It is often the same group of prestigious professors, often also editors of those top scientific journals or their close associates/friends, who block the publication of others’ scientific breakthroughs that would have conflicts with their own research or interests. If there are multi-millions of grants, academic rank, salaries, job security, and lab spaces on the line, it is hard to imagine how much the scientific integrity and professional ethics would really weigh against those big material benefits, particularly under a confidential review system where the reviewers basically can do whatever they like, say whatever they want, even things far away from the truth, without any concerns to get caught.

The politicization of top scientific journals has not gone unnoticed in the stem cell community. It is not any secret to the scientific community that the biggest stem cell scam of the last few years is the induced pluripotent stem cells (iPS cells) made by the Japanese scientist Shinya Yamanaka who put multiple oncogenes into the skin cells, which was first published in Cell in 2007, widely proliferated in Nature, Science, Cell Stem Cell, and has become almost the only publishable fake stem cell research in Cell Stem Cell in the last few years, where most of the promoters of iPS cells are also the editors. It is not so difficult to tell in the first place that the idea of Yamanaka’s iPS cells is in fact flawed because it is common scientific knowledge taught in all the universities that cancer is caused by turning on oncogenes in adult cells, so iPS cells are actually abnormal cancer cells, not stem cells. Yamanaka’s iPS cells are actually the politicization of sciences by a group of prestigious university professors to meet Bush administration’s demand for alternative for pluripotent human embryonic stem cells (hESCs). Yamanaka’s iPS cells tell us a true story where science has become secondary to the political purpose, a true story of politicization of stem cell research. Yamanaka’s iPS cells were promulgated by more than 100 major international news agencies as the “biggest breakthrough of stem cell research”, as the “ethical alternative for human embryonic stem cells”. However, Yamanaka has never provided any scientific evidence that iPS cells are stem cells because it requires very difficult and time-consuming self-renewal analysis that is commonly accepted as the proof of any stem cells, nor anything else that Yamanaka or those promoters of iPS cells said about the iPS cells as the alternative for hESCs is true or has any scientific proof. There are many scientific reports to show iPS cells actually have more genetic defects than cloned embryos, which are known for abnormal. There are many scientific evidences to show iPS cells are actually flawed, however, these real scientific research and data were not so widely promulgated since they did not fit the political purposes of some interest groups. How did Yamanaka, who is the editor of Cell/CSC and also has close relationship with the presidents and other top officials of international society for stem cell research (ISSCR), skip the required self-renewal experiments and get his fake stem cell research published in Cell in 2007 without even providing the slightest scientific data for self-renewal that has been mandated for the proof of stem cells by anyone else? And how did Yamanaka win the Nobel prize with such fake stem cell research without any solid scientific evidences for any breakthroughs in 2012? It is interesting if we pay little bit attention to the timing of Yamanaka iPS cells and the timing of his Nobel prize as well as the scope of their promulgations by more than 100 major international news agencies as the “biggest breakthrough of stem cell research”, as the “ethical alternative for human embryonic stem cells”, which were all closely aligned with the political gains of those against hESC research. Scientifically, those flawed alternatives for hESCs, including Yamanaka iPS cells, later trans-differentiation of adult cells, and most recently cloned embryos, are disasters for stem cell research. If we look at how much taxpayers’ money has gone into such fake stem cell research or politicization of stem cell research of those interest groups, the magnitude is huge. Since 2007, about $5-10 billions of NIH (National Institutes of Health), CIRM (California Institute for Regenerative Medicine), and investor funds have gone into such flawed ideas, nothing has come out of it, except more and more reports to prove the flaws of such adult alternatives that were in fact flawed in the first place. Ironically, it is Obama administration, not Bush administration, has provided the most funding from NIH to those interest groups’ fake stem cell research or politicization of stem cell research by Bush administration. Needless to say, most of the beneficiaries are the promoters of iPS cells, many sitting on the editorial board of top scientific journals, including Cell Stem Cell, the official journal of ISSCR.

When it comes to tell stem cell scams from stem cell research, my more than 20 years of scientific training and knowledge have really helped me. Unfortunately, it is hard to say the same to the general public and investors who mostly do not have the same level of scientific knowledge to tell the truth from false about stem cell research. Maybe it would help if you pay attention to those warning signs, such as if the science has become secondary to the purpose, if the scientist or professor you think you trust talks like a politician, if the scientist or professor you think you trust is saying something without any scientific data, if the professor is talking about a big breakthrough but has absolutely nothing to show what the breakthrough is, if the physician or company is selling treatment or cure but has nothing to show that they can do that, if the company is saying their cells can repair heart but has nothing to show their cells can become heart muscle cells, if the professor begins to substitute data with some not so difficult drawings, etc. This opinion is written in response to reader’s suggestion below.

From: Lana Reese [mailto:lanamreese@gmail.com]
Sent: Tuesday, December 31, 2013 11:16 AM
To: contacts@SDRMI.org
Subject: New controversies in the Research/Publishing Process for Voive of Regenerative medicine readers

Hi

I hope all is well.

I wanted to pass along a couple links to stories that might be a good fit for Voive of Regenerative medicine, or could at least be valuable conversation starters for your social followings. It seemed particularly relevant given your position in quickly evolving field of stem cells.

Recently, Nobel Prize Winner Randy Schekman and former science editor Richard Smith called into question current practices of the scientific publishing process, underscoring a growing need for change. With these debates being such hot topics, I thought your readers would enjoy hearing your take on it, specifically the relevance that change could have for the industry moving forward.

Here are the links to the two stories, which delve into the problems and possible solutions facing scientific publishing:


Happy holidays and I’d love to see your opinion on the articles!
Best,

Lana

Editorial: The Designation of Human Embryonic Stem Cell Cardiac Therapy Derivatives for Human Trials

Editorial: The Designation of Human Embryonic Stem Cell Cardiac Therapy Derivatives for Human Trials

Dr. Parsons, founder of San Diego Regenerative Medicine Institute and Xcelthera, INC., has discussed scientific breakthroughs in human embryonic stem cell (hESC) research in her two recent Editorials, titled “Cellular medicine for the heart - the pharmacologic utility and capacity of human cardiac stem cells” at J. Clinic. Exp. Cardiology 2013;S11-e001 (doi: 10.4172/2155-9880.S11-e001) & “Reviving cell-based regenerative medicine for heart reconstitution with efficiency in deriving cardiac elements from pluripotent human embryonic stem cells” at Cardiol. Pharmacol 2013;2(3):e112 (doi: 10.4172/2329-6607.1000e112). Such breakthrough developments have demonstrated the direct pharmacologic utility and capacity of hESC cell therapy derivatives for human CNS and myocardium regeneration, thus, presented the hESC cell therapy derivatives as a powerful pharmacologic agent of cellular entity for CNS and heart repair.

Cardiovascular disease is a major health problem and the leading cause of death in the Western world. About 600,000 people die of heart disease in the United States every year–that’s 1 in every 4 deaths. The estimated costs of cardiovascular disease for the overall US population are approximately $190 billion annually. Currently, there is no treatment option or compound drug of molecular entity that can change the prognosis of cardiovascular disease. Given the limited capacity of the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal heart tissue and function for heart disease and failure. However, traditional sources of cells for therapy in existing markets have been adult stem cells isolated from tissues or artificially reprogrammed from adult cells, which all have the historical shortcomings of limited capacity for renewal and repair, accelerated aging, and immune-rejection following transplantation. In addition, artificially reprogrammed adult cells have the major drawbacks of extremely low efficiencies and genetic defects associated with high risks of cancers, which have severely limited their utility as viable therapeutic approaches. In the adult heart, the mature contracting cardiac muscle cells, known as cardiomyocytes, are terminally differentiated and unable to regenerate. There is no scientific evidence that adult stem/precursor/progenitor cells derived from mature tissues, such as bone marrow, cord blood, umbilical cord, mesenchymal stem cells, patients’ heart tissue, placenta, or fat tissue, are able to give rise to the contractile heart muscle cells following transplantation into the heart. Despite numerous reports about cell populations expressing stem/precursor/progenitor cell markers identified in the adult hearts, the minuscule quantities and growing evidences indicating that they are not genuine heart cells and that they give rise predominantly to non-functional smooth muscle cells rather than functional contractile cardiomyocytes have caused skepticism if they can potentially be harnessed for cardiac repair. Although a vast sum of government and private funding has been spent on looking for adult alternates, such as reprogramming and trans-differentiation of fibroblasts or mature tissues, so far, only human cardiac stem/precursor/progenitor cells derived from embryo-originated hESCs have shown such cellular pharmacologic utility and capacity adequate for myocardium regeneration in pharmaceutical development of stem cell therapy for the damaged heart.


Recent milestone advances and medical innovations in hESC research enable high efficient direct conversion of non-functional pluripotent hESCs into a large supply of clinical-grade high purity functional human neuronal cells or heart muscle cells for developing safe and effective stem cell therapies as treatments or cures for a wide range of neurological and cardiovascular diseases. Currently, these hESC neuronal and cardiomyocyte cell therapy derivatives are the only available human cell sources in commercial scales with adequate cellular pharmacologic utility and capacity to regenerate CNS neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting. Transforming non-functional pluripotent hESCs into fate-restricted functional human cell therapy derivatives or products allows moving stem cell research from current studies in animals towards human trials. 

Friday, July 19, 2013

Editorial: Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration

San Diego Regenerative Medicine Institute and Xcelthera announce Dr. Parsons’ Editorial, titled “Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration” (doi: 10.4172/cpo.1000e110), published in current issue of The International Open Access Journal of Cardiovascular Pharmacology.

Given the limited capacity of the heart muscle for self-repair after birth, transplantation of cardiomyocyte stem/precursor/progenitor cells holds enormous potential in cell replacement therapy for cardiac repair. However, the lack of a clinically-suitable human cardiomyocyte stem/precursor/progenitor cell source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart, either by endogenous cells or by cell-based transplantation or cardiac tissue engineering. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing human embryonic stem cell (hESC)-based therapy for heart disease and failure. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. In addition, undefined foreign or animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic. Recent technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. Such milestone advances and medical innovations in hESC research enable direct conversion of pluripotent hESCs into a large supply of homogeneous populations of clinical-grade hESC neuronal and heart cell therapy products for developing safe and effective stem cell therapies. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting. This novel small molecule direct induction approach renders a cascade of neural or cardiac lineage-specific progression directly from the pluripotent state of hESCs, providing much-needed in vitro model systems for investigating the genetic and epigenetic programs governing the human embryonic CNS or heart formation. Please read Dr. Parsons’ editorial at http://www.esciencecentral.org/journals/ArchiveCPO/currentissueCPO.php.

Direct Conversion of Pluripotent Human Embryonic Stem Cells into Functional Cell Therapy Derivatives Brings Cell-Based Regenerative Medicine to a Turning Point

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ review article, titled “Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine”, in British Biotechnology Journal at http://www.sciencedomain.org/issue.php?iid=243&id=11. In this review article, Dr. Parsons gives an insight view on recent advances and breakthroughs in human embryonic stem cell (hESC) research that have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-based regenerative medicine to a turning point.

Human stem cell therapy derivatives are extremely attractive for therapeutic development because they have direct pharmacologic utility in clinical applications, unlike any cells originated from animals and other lower organisms that are only useful as research materials. The human stem cell is emerging as a new type of pharmacologic agent of cellular entity in cell-based regenerative medicine, because human stem cell therapy derivatives have the potential for human tissue and function restoration that the conventional drug of molecular entity lacks. The ability of a human stem cell, by definition, to both self-renew and differentiation makes it a practically inexhaustible source of replacement cells for many devastating or fatal diseases that have been considered as incurable, such as neurodegenerative diseases and heart diseases. The pharmacologic activity of human stem cell therapy derivatives is measured by their extraordinary cellular ability to regenerate the tissue or organ that has been damaged or lost. In this regard, the pharmacologic utility of human stem cells cannot be satisfied only by their chaperone activity, if any, to produce trophic or protective molecules to rescue existing endogenous host cells that can simply be achieved by a small molecule or a drug of molecular entity. There is a large unmet healthcare need to develop human embryonic stem cell (hESC)-based stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Clinical applications of hESC therapy derivatives provide the right alternative for many incurable diseases and major health problems that the conventional mode of drugs and treatments cannot.

We must bear in mind that the pluripotent hESC itself cannot be used for therapeutic applications. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, which yields embryoid body (EB) consisting of a mixed population of cell types that may reside in three embryonic germ layers and results in inefficient, incomplete, and uncontrollable differentiation that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. Growing evidences indicate that incomplete lineage specification of pluripotent cells via multi-lineage differentiation often resulted in poor performance of such stem cell derivatives and/or tissue-engineering constructs following transplantation. In addition, most currently available hESC lines were derived and maintained on animal feeder cells and proteins, therefore, such hESCs have been contaminated with animal biologics and unsuitable for clinical application. Without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies and profiling of hESC differentiating multi-lineage aggregates have compromised their implications to molecular controls in human embryonic development.

Recent advances and technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation of clinically-suitable stable hESC lines from human blastocysts that have never been contaminated by animal cells and proteins, and direct conversion of such pluripotent hESCs into a large supply of clinical-grade functional human neuronal or cardiomyocyte therapy derivatives to be translated to patients for CNS or heart repair. Without an understanding of the essential developmental components for sustaining hESC pluripotence and self-renewal, hESC lines are at risk for becoming unhealthy and unstable after prolonged culturing under animal feeders, feeder-conditioned media, or artificially-formulated chemically-defined conditions. Resolving minimal essential requirements for sustaining embryonic pluripotence allows all poorly-characterized and unspecified biological additives, components, and substrates in the culture system, including those derived from animals, to be removed, substituted, or optimized with defined human alternatives for de novo derivation and long-term maintenance of GMP-quality xeno-free stable hESC lines and their human therapy derivatives. Formulation of minimal essential defined conditions renders pluripotent hESCs be directly and uniformly converted into a specific neural or cardiac lineage by small signal molecule induction. Such milestone advances and medical innovations in hESC research enable generation of a large supply of high purity clinical-grade hESC neuronal and heart muscle cell therapy products as powerful cellular medicines that can offer pharmacologic utility and capacity for CNS and heart regeneration that no conventional drug of molecular entity can. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting. The availability of human neuronal and cardiomyocyte therapy derivatives in high purity and large quantity with adequate potential for CNS and myocardium regeneration will facilitate CNS and myocardial tissue-engineering and accelerate the development of safe and effective cell-based therapy to resolve these major health problems. Further improving policy making and funding situation for hESC research would open up a new dimension of cell therapy-based future medicine to provide new medical treatments for many devastating and life-threatening diseases and injuries. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products, bringing cell-based regenerative medicine to a turning point. Please read Dr. Parsons’ full open access article at http://www.sciencedomain.org/issue.php?iid=243&id=11.

Wednesday, June 19, 2013

Embedding Lineage-Specific Developmental Programs into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells Offers Efficiency in Deriving Cell Therapy Products for the Future of Regenerative Medicine

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ review article, titled “Embedding the Future of Regenerative Medicine into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells”, in Annual Review & Research in Biology at http://www.sciencedomain.org/issue.php?iid=239&id=9. In this review article, Dr. Parsons gives an insight view on the human stem cell epigenomes in discerning the intrinsic plasticity and regenerative potential of human stem cell derivatives from various sources as well as recent advances on uncovering the developmental programs embedded in neural and cardiac lineage-specific differentiation of pluripotent human embryonic stem cells (hESCs) that lead to efficiency in deriving neural and cardiac elements for cell-based therapies.

Human stem cells are extremely attractive for therapeutic development because they have direct pharmacologic utility in clinical applications, unlike any cells originated from animals and other lower organisms that are only useful as research materials. The human stem cell is emerging as a new type of drug of cellular entity that can offer pharmacological utility and capacity for human tissue and function restoration that the conventional compound drug of molecular entity lacks. However, to date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost central nervous system (CNS) structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent hESCs, derived from the pluripotent inner cell mass or epiblast of the human blastocyst, have both the unconstrained capacity for long-term stable undifferentiated growth in culture and the intrinsic potential for differentiation into all somatic cell types in the human body, holding tremendous potential for restoring human tissue and organ function. Given the limited capacity of the CNS and heart for self-repair, transplantation of hESC neuronal and heart cell therapy derivatives holds enormous potential in cell replacement therapy for neurodegenerative and heart diseases that cost the healthcare system > $500 billions annually. There is a large unmet healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for normal tissue and function restoration in many major health problems. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by conventional approaches for generating functional cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation. Growing evidences indicate that incomplete lineage specification of pluripotent cells via multi-lineage differentiation often resulted in poor performance of such stem cell derivatives and tissue-engineering constructs following transplantation. The development of better differentiation strategies that permit to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to desired phenotypes is vital for realizing the therapeutic potential of pluripotent hESCs.

The eukaryotic genome is packaged into chromatin, a nucleoprotein complex in which the DNA helix is wrapped around an octamer of core histone proteins to form a nucleosomal DNA structure, known as nucleosome, that is further folded into higher-order chromatin structures with the involvement of other chromosomal proteins. Chromatin modifications, such as DNA methylation and histone modifications, serve as important epigenetic marks for active and inactive chromatin states, thus the principal epigenetic mechanism in early embryogenesis. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations reside in chromatin modifications that shape the respective epigenomes of their derivation routes. The broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin. The hESCs are not only pluripotent, but also incredibly stable and positive, as evident by that only the positive active chromatin remodeling factors, but not the negative repressive chromatin remodeling factors, can be found in the pluripotent epigenome of hESCs. The normality and positivity of hESC open epigenome also differentiate pluripotent hESCs from any other stem cells, such as the induced pluripotent stem cells (iPS cells) reprogrammed from adult cells with known oncogenes and the tissue-resident stem cells. Somatic cell nuclear transfer and transcription-factor-based reprogramming have been used to revert adult cells to an embryonic-like state with extremely low efficiencies. Although pluripotent, the iPS cells and ESC derived from cloned embryos by somatic nuclear transfer are made from adult cells, therefore, adult cell-originated pluripotent cells carry many negative repressive chromatin remodeling factors and unerasable genetic imprints of adult cells that pluripotent hESCs do not have. Somatic cell nuclear transfer and factor-based reprogramming are incapable of restoring a correct epigenetic pattern of pluripotent hESCs, which accounts for abnormal gene expression, accelerated senescence, not graftable, and immune-rejection following transplantation of reprogrammed cells. These major drawbacks have severely impaired the utility of reprogrammed or deprogrammed or direct or trans-differentiated somatic cells as viable therapeutic approaches.


Using hESCs to develop cellular medicine for the brain and the heart must first transform pluripotent hESCs into CNS or heart fate-restricted cell therapy derivatives. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. This technology breakthrough enables high efficient direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate pharmacologic capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate pharmacologic capacity to regenerate neurons and contractile heart muscles that no conventional drug of molecular entity or tissue-derived stem cells can. Embedding lineage-specific genetic and epigenetic programs into the open epigenomic landscape of pluripotent hESCs offers a new dimension for direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. Please read Dr. Parsons’ full open access article at http://www.sciencedomain.org/issue.php?iid=239&id=9.

Friday, May 31, 2013

CIRM Employs Negative Reviewers of No Scientific Integrity to Make Dishonest Comments and Scores to Block Prop71 Stem Cell Research for Funding and Cover Up COI

To understand why billions of Prop71 have flowed into conflicts of interest (COI) but not stem cell research from CIRM unobscurely, it may help to look into CIRM flawed review process, particularly the part that has been forbidden by CIRM internal COI to disclose to the public, covered up as CIRM pre-application or LOI. It is interesting to see CIRM president Alan Trounson’ very public demand for his $70 million alpha clinic proposal while, unseen by the public, he is so evidently negligent or even negative about stem cell research and therapy in handling CIRM flawed grant review process as CIRM president. The only problem is that, so far, CIRM has not had one FDA-approved stem cell therapy, not even any CIRM sponsored IND or clinical trials. Without clinically-suitable human stem cells or FDA-approved stem cell therapy, Alan Trounson’s alpha clinics would be no different from those stem cell con man’s clinics hunted by FBI. It would turn out to be just another way for Alan Trounson to get $70 million freebies for CIRM COI, while under the cover he has been deliberately blocking those real beneficial proposals that would provide stem cell therapy for his alpha clinics using CIRM COI flawed review process with his apparent consent.

If ICOC’s COI is only speculation in public, COI in CIRM grant review is monopoly, even to the extent of extortion. Therefore, it is no surprise CIRM has been very resistant to be transparent in its grant review. So far, it seems that CIRM reviewers have been only capable of making negative comments that are so full of false statement, factual error, bias or predisposition, COI that have comprised the integrity and credibility of any advices provided by the reviewers. It is quite shocking that CIRM reviewers of no scientific integrity usually could not note any strength of hESC research proposal and intentionally gave false or biased or dishonest comments and scores against scientific evidences that did not reflect the overall impact and scientific merit of hESC grant applications (see hESC grant title and summary below for example). Our proposal shown below is to understand molecular mechanism in human embryonic stem cell neuronal differentiation using novel lineage-specific differentiation technique in hESC research breakthrough. Such technique has never been described before us. Only RA effect on hESC differentiating multi-lineage embryoid body has been described before, but the effects are small, and molecular mechanism in human and mouse ESC is totally different. There is nothing in our proposal about iPS cells and some other irrelevant comments made by CIRM reviewers. We have written to CIRM president/vice president, CIRM, ICOC multiple times about such flawed reviews from CIRM reviewers before, however, it seems that CIRM president/vice president or chair or ICOC have never been able to address such serious issues as CIRM reviewers’ COI or scientific misconduct, deliberately brushed it off, never responded to our complaints about CIRM flawed reviews or COI in CIRM review, and covered it up by consent to reviewers’ COI or false statement or flawed review. Considering many of CIRM ICOC members are leaders, physicians, Deans, and Presidents who know more than anyone else how serious a issue of scientific misconduct is in their own institutions, particularly provided by CIRM review comments for unmistakenable evidences, it would be detrimental for us to think that CIRM or ICOC or CIRM president/vice president or chair have been actually behind CIRM reviewers’ COI, false statement, or scientific misconduct by deliberately avoiding to address CIRM flawed grant review process.

RFA 13-02, RB5-07199:
Molecular Controls in Human Embryonic Stem Cell (hESC) Neuronal Lineage Specification

The hESCs provide a powerful in vitro model system to investigate molecular controls in human embryonic neurogenesis as well as an unlimited source to generate the diversity of human neuronal cell types for CNS repair. However, realizing the potential of hESC derivatives has been hindered by conventional approaches for generating neuronal cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific neuronal or cardiac lineage by small molecule induction. This technology breakthrough enables well-controlled efficient neuronal lineage-specific differentiation direct from the pluripotent state of hESCs. In this project, this novel hESC model of neuronal lineage-specific progression will be characterized and used for genome-wide genetic and epigenetic profiling to generate a comprehensive knowledge of developmental regulators and networks for identification of molecular controls in hESC neuronal lineage specification. Fulfilling the goal of this project will be provide a comprehensive understanding of molecular neurogenesis in human embryonic development, thereby, reveal potential molecular and cellular therapeutic targets for the prevention and treatment of CNS disorders. The outcome of this project will have a transformative impact on a broad area of biomedical sciences and public health.  


From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, May 24, 2013 12:58 PM
To: parsons@sdrmi.org
Subject: CIRM Basic Biology V Awards
Dear Dr. Parsons:
Thank you for submitting your proposal under the CIRM RFA 13-02: Basic Biology V Awards. After careful consideration, your PreApp was not selected for further review under this RFA.
The goal of the PreApp process is to identify proposals that are the most responsive to the RFA objectives and likely to be competitive. For this competition we received over 340 PreApps and selected about 60 for a full application. The process was designed to handle a large volume of proposals and to ensure a rapid turn-around on the review. Reviewers may provide brief comments that highlight strengths and weaknesses where appropriate. The comments are not comprehensive and do not necessarily provide all the reasons for an invitation or denial. Each application is assigned to 3 independent reviewers and each reviewer assesses approximately 20-30 PreApps within their area of expertise and scores the applications on a scale of 1 to 100, 100 being the most meritorious. CIRM scientific staff further assesses proposals to ensure that projects meet eligibility requirements and are responsive to the RFA. CIRM invites the most highly ranked and responsive PreApps as determined by the external scientific reviewers and CIRM science officers.
The summary below shows the final score for your PreApp and comments provided by reviewers.
We thank you for your interest, and we encourage you to respond to future CIRM initiatives. We look forward to your future applications to CIRM. If you have any questions about the review please feel free to contact me.
Sincerely,
Gil Sambrano
Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107

Phone: 415-396-9103
gsambrano@cirm.ca.gov

SUMMARY OF REVIEW
Overall Scientific Score: 33.33
Comments provided by reviewers:
Comments 1:
Strengths:
            The use of an in-vivo assay in Milestone 3 is very significant as it validates the in-vitro results of all the other Milestones.
Weaknesses:
            The direct conversion of hESCs to neuronal derivatives has already been extensively described by many different laboratories. (our response: the reviewer’s statement is false & against scientific evidences. The fact is the direct conversion of hESCs from the pluripotent state to neuronal derivatives has never been done by any laboratories before us.)
            It has been shown that inhibition of the TGFB pathway by SB and LDN small compound is sufficient to robustly induce conversion to telencephalic. (our response: The reviewer did not provide the fact that it was induced from neuroepithelial cells isolated from embryoid bodies (EBs) in extremely low efficiency by University of Connecticut & groups connected to CIRM vice president/UC connect/Sanford/UC. Our study overcomes their shortcoming to generate neurons direct from hESCs in high efficiency and purity, not isolated from EB.  The fact the reviewer did not disclose shows that this review had conflicts of interest (COI) and intentionally gave false or biased or dishonest comments against scientific evidences, which has affected the integrity of advice provided by this reviewer).
            The use of RA is sub-optimum as it as it generates random sets of neurons, which will make collective data analysis useless. (Our response: the reviewer’s statement is false & against scientific evidences. RA is optimized to induce neuroectoderm and neuronal differentiation from hESCs to a large supply of neuronal cell type and subtypes, which is critical for collecting data for analysis of molecular mechanism in hESC neuronal lineage specification.)

Comments 2: (our response: our proposal is to investigate molecular mechanism in hESC neuronal lineage-specific differentiation and has nothing to do with iPS cells and the negative comments of this reviewer (see title & summary). The reviewers’ comments are false, which show COI since this review could not note any strength of this hESC proposal and intentionally gave false or biased or dishonest comments against scientific evidences, and which has affected the integrity of advice provided by this reviewer).
Weaknesses:
- This protocol for differentiating human iPSCs into neurons has not particular advantages respect to others already present in the literature, while having some substantial drawbacks:
1) this protocol is not designed to generate one particular neuronal subtype while generating a variety of very different neurons. It is not clear which relation is existing between DA and spinal cord neurons which are both generated by this same protocol.
2) it is not explained which particular type of DA or spinal cord neurons are generated with this protocol. Are DA neurons patterned as ventral mesencephalic Pitx3+ neurons? This is a crucial information for generating therapeutic relevant neurons.
3) Retinoic Acid (RA) it is a well-known inducer of caudal neuronal subtypes. It is therefore unclear how DA neurons can be specified in this particular regimen
4) Preliminary data are missing showing electrophysiological maturation and activity of iPSC-derived neurons
Considering these pitfalls, caution is required in employing this protocol in large extent and a better characterization of the differentiated neurons is necessary to validate the system.

Comments 3: (our response: our proposal is to investigate molecular mechanism in hESC neuronal lineage-specific differentiation using a novel technology by small signal molecule induction. The reviewer’s comments are vague, did not give any specifics. It is commonly known that miRNAs are governors of regulatory circuits. The reviewers’ comments are biased, which show COI since this review could not note any strength and apparent novelty of this hESC proposal and intentionally gave false or biased or dishonest comments against scientific evidences, and which has affected the integrity of advice provided by this reviewer).
novelty of this application not at all clear
many vague, sweeping statements about the transformative nature of the work, but very little focus
not at all clear how regulatory circuits will emerge from miRNA profiling

CIRM Comments:
NA
Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107

(415) 396-9103